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Suppression of nonsense mutations as a therapeutic approach to treat genetic diseases

Advanced Review

David M. Bedwell, Kim M. Keeling

Published Online: Jul 06 2011

DOI: 10.1002/wrna.95

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Abstract Suppression therapy is a treatment strategy for genetic diseases caused by nonsense mutations. This therapeutic approach utilizes pharmacological agents that suppress translation termination at in‐frame premature termination codons (PTCs) to restore translation of a full‐length, functional polypeptide. The efficiency of various classes of compounds to suppress PTCs in mammalian cells is discussed along with the current limitations of this therapy. We also elaborate on approaches to improve the efficiency of suppression that include methods to enhance the effectiveness of current suppression drugs and the design or discovery of new, more effective suppression agents. Finally, we discuss the role of nonsense‐mediated mRNA decay (NMD) in limiting the effectiveness of suppression therapy, and describe tactics that may allow the efficiency of NMD to be modulated in order to enhance suppression therapy. WIREs RNA 2011 2 837–852 DOI: 10.1002/wrna.95 Correction added on July 13 2011, after first online publication. Figure 5 was incorrect and has been replaced. This article is categorized under: Translation > Translation Mechanisms RNA in Disease and Development > RNA in Disease

Translation termination. During translation termination, eukaryotic release factors 1 and 3 (eRF1 and eRF3) bind the pretermination complex with a stop codon located in the ribosomal A site. eRF1 mediates the initial recognition of the stop codon. GTP hydrolysis by eRF3 finalizes stop codon recognition and facilitates polypeptide chain release.

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Structure of the nonsense‐mediated mRNA decay (NMD) inhibitor, NMDI‐1.

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A simplified model of mammalian nonsense‐mediated mRNA decay (NMD).

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Structures of non‐aminoglycoside compounds that suppress translation termination at premature termination codons.

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Structures of conventional aminoglycosides and novel synthetic aminoglycosides. The novel synthetic aminoglycoside derivatives shown contain structural components of conventional aminoglycosides (shaded and labeled (A)–(C)) that are predicted to enhance suppression nonsense mutations while decreasing their nonspecific interactions.

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Structures of gentamicin congeners.

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Comparison of translation termination at natural versus premature stop codons. (a) Termination at natural stop codons. Termination efficiency at natural stop codons located near the 3′ end of mRNAs is enhanced by interactions between eukaryotic release factor 3 (eRF3) and poly(A) binding protein (PABP). (b) Termination at premature stop codons. eRF3 and PABP cannot interact efficiently because of the spatial distance between premature termination codons and the poly(A) tail of the mRNA where PABP binds, thus reducing the efficiency of termination. The absence of this interaction is thought to result in ribosome pausing at the premature stop codon, making them more susceptible to suppression.

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Suppression of translation termination. During the suppression of a premature stop codon, a near‐cognate aminoacyl tRNA pair at two of the three bases of the stop codon. The amino acid carried by the near‐cognate tRNA is added to the polypeptide chain and translation resumes in the proper reading frame until the natural stop codon is reached.

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References

Frischmeyer, PA, Dietz, HC. Nonsense‐mediated mRNA decay in health and disease. Hum Mol Genet 1999, 8:1893–1900.
Rodnina, MV, Gromadski, KB, Kothe, U, Wieden, HJ. Recognition and selection of tRNA in translation. FEBS Lett 2005, 579:938–942.
Zhouravleva, G, Frolova, L, Le Goff, X, Le Guellec, R, Inge‐Vechtomov, S, Kisselev, L, Philippe, M. Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3. EMBO J 1995, 14:4065–4072.
Song, H, Mugnier, P, Das, AK, Webb, HM, Evans, DR, Tuite, MF, Hemmings, BA, Barford, D. The crystal structure of human eukaryotic release factor eRF1—mechanism of stop codon recognition and peptidyl‐tRNA hydrolysis. Cell 2000, 100:311–321.
Frolova, L, Le Goff, X, Zhouravleva, G, Davydova, E, Philippe, M, Kisselev, L. Eukaryotic polypeptide chain release factor eRF3 is an eRF1‐ and ribosome‐dependent guanosine triphosphatase. RNA 1996, 2:334–341.
Salas‐Marco, J, Bedwell, DM. GTP hydrolysis by eRF3 facilitates stop codon decoding during eukaryotic translation termination. Mol Cell Biol 2004, 24:7769–7778.
Fearon, K, McClendon, V, Bonetti, B, Bedwell, DM. Premature translation termination mutations are efficiently suppressed in a highly conserved region of yeast Ste6p, a member of the ATP‐binding cassette (ABC) transporter family. J Biol Chem 1994, 269:17802–17808.
Cassan, M, Rousset, JP. UAG readthrough in mammalian cells: effect of upstream and downstream stop codon contexts reveal different signals. BMC Mol Biol 2001, 2:3.
Manuvakhova, M, Keeling, K, Bedwell, DM. Aminoglycoside antibiotics mediate context‐dependent suppression of termination codons in a mammalian translation system. RNA 2000, 6:1044–1055.
McCaughan, KK, Brown, CM, Dalphin, ME, Berry, MJ, Tate, WP. Translational termination efficiency in mammals is influenced by the base following the stop codon. Proc Natl Acad Sci USA 1995, 92:5431–5435.
Tate, WP, Poole, ES, Horsfield, JA, Mannering, SA, Brown, CM, Moffat, JG, Dalphin, ME, McCaughan, KK, Major, LL, Wilson, DN. Translational termination efficiency in both bacteria and mammals is regulated by the base following the stop codon. Biochem Cell Biol 1995, 73:1095–1103.
Keeling, KM, Brooks, DA, Hopwood, JJ, Li, P, Thompson, JN, Bedwell, DM. Gentamicin‐mediated suppression of Hurler syndrome stop mutations restores a low level of α‐L‐iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Hum Mol Genet 2001, 10:291–299.
Chernikov, VG, Terekhov, SM, Krokhina, TB, Shishkin, SS, Smirnova, TD, Kalashnikova, EA, Adnoral, NV, Rebrov, LB, Denisov‐Nikol`skii, YI, Bykov, VA. Comparison of cytotoxicity of aminoglycoside antibiotics using a panel cellular biotest system. Bull Exp Biol Med 2003, 135:103–105.
Keeling, KM, Bedwell, DM. Clinically relevant aminoglycosides can suppress disease‐associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system. J Mol Med 2002, 80:367–376.
Amrani, N, Ganesan, R, Kervestin, S, Mangus, DA, Ghosh, S, Jacobson, A. A faux 3`‐UTR promotes aberrant termination and triggers nonsense‐mediated mRNA decay. Nature 2004, 432:112–118.
Hoshino, S, Imai, M, Kobayashi, T, Uchida, N, Katada, T. The eukaryotic polypeptide chain releasing factor (eRF3/GSPT) carrying the translation termination signal to the 3′‐poly(A) tail of mRNA. Direct association of erf3/GSPT with polyadenylate‐binding protein. J Biol Chem 1999, 274:16677–16680.
Ivanov, PV, Gehring, NH, Kunz, JB, Hentze, MW, Kulozik, AE. Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways. EMBO J 2008, 27:736–747.
Singh, G, Rebbapragada, I, Lykke‐Andersen, J. A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense‐mediated mRNA decay. PLoS Biol 2008, 6:e111.
Atkins, JF, Baranov, PV, Fayet, O, Herr, AJ, Howard, MT, Ivanov, IP, Matsufuji, S, Miller, WA, Moore, B, Prere, MF, et al. Overriding standard decoding: implications of recoding for ribosome function and enrichment of gene expression. Cold Spring Harb Symp Quant Biol 2001, 66:217–232.
Namy, O, Hatin, I, Rousset, JP. Impact of the six nucleotides downstream of the stop codon on translation termination. EMBO Rep 2001, 2:787–793.
Dalphin, ME, Stockwell, PA, Tate, WP, Brown, CM. TransTerm, the translational signal database, extended to include full coding sequences and untranslated regions. Nucleic Acids Res 1999, 27:293–294.
Frischmeyer, PA, van Hoof, A, O`Donnell, K, Guerrerio, AL, Parker, R, Dietz, HC. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science 2002, 295:2258–2261.
Kong, J, Liebhaber, SA. A cell type‐restricted mRNA surveillance pathway triggered by ribosome extension into the 3′ untranslated region. Nat Struct Mol Biol 2007, 14:670–676.
Tok, JB, Bi, L. Aminoglycoside and its derivatives as ligands to target the ribosome. Curr Top Med Chem 2003, 3:1001–1019.
Recht, MI, Douthwaite, S, Puglisi, JD. Basis for prokaryotic specificity of action of aminoglycoside antibiotics. EMBO J 1999, 18:3133–3138.
Lynch, SR, Puglisi, JD. Structural origins of aminoglycoside specificity for prokaryotic ribosomes. J Mol Biol 2001, 306:1037–1058.
Salas‐Marco, J, Bedwell, DM. Discrimination between defects in elongation fidelity and termination efficiency provides mechanistic insights into translational readthrough. J Mol Biol 2005, 348:801–815.
Dietz, HC. New therapeutic approaches to mendelian disorders. N Engl J Med 2011, 363:852–863.
Keeling, KM, Bedwell, DM. Recoding therapies for genetic diseases. In: Atkins, JF, Gesteland, RF, eds. Recoding: Expansion of Decoding Rules Enriches Gene Expression. New York: Springer Publishing; 2010.
Linde, L, Kerem, B. Introducing sense into nonsense in treatments of human genetic diseases. Trends Genet 2008, 24:552–563.
Clancy, JP, Bebok, Z, Ruiz, F, King, C, Jones, J, Walker, L, Greer, H, Hong, J, Wing, L, Macaluso, M, et al. Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med 2001, 163:1683–1692.
Clancy, JP, Rowe, SM, Bebok, Z, Aitken, ML, Gibson, R, Zeitlin, P, Berclaz, P, Moss, R, Knowles, MR, Oster, RA, et al. No detectable improvements in CFTR by nasal aminoglycosides in CF patients with stop mutations. Am J Respir Cell Mol Biol 2007, 37:57–66.
Wilschanski, M, Famini, C, Blau, H, Rivlin, J, Augarten, A, Avital, A, Kerem, B, Kerem, E. A pilot study of the effect of gentamicin on nasal potential difference measurements in cystic fibrosis patients carrying stop mutations. Am J Respir Crit Care Med 2000, 161(3 Pt 1):860–865.
Wilschanski, M, Yahav, Y, Yaacov, Y, Blau, H, Bentur, L, Rivlin, J, Aviram, M, Bdolah‐Abram, T, Bebok, Z, Shushi, L, et al. Gentamicin‐induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N Engl J Med 2003, 349:1433–1441.
Dunant, P, Walter, MC, Karpati, G, Lochmuller, H. Gentamicin fails to increase dystrophin expression in dystrophin‐deficient muscle. Muscle Nerve 2003, 27:624–627.
Politano, L, Nigro, G, Nigro, V, Piluso, G, Papparella, S, Paciello, O, Comi, LI. Gentamicin administration in Duchenne patients with premature stop codon. Preliminary results. Acta Myol 2003, 22:15–21.
James, PD, Raut, S, Rivard, GE, Poon, MC, Warner, M, McKenna, S, Leggo, J, Lillicrap, D. Aminoglycoside suppression of nonsense mutations in severe hemophilia. Blood 2005, 106:3043–3048.
Kellermayer, R, Szigeti, R, Keeling, KM, Bedekovics, T, Bedwell, DM. Aminoglycosides as potential pharmacogenetic agents in the treatment of Hailey‐Hailey disease. J Invest Dermatol 2006, 126:229–231.
Martin, R. On the relationship between preferred termination codon contexts and nonsense suppression in human cells. Nucleic Acids Res 1994, 22:15–19.
Moestrup, SK, Cui, S, Vorum, H, Bregengard, C, Bjorn, SE, Norris, K, Gliemann, J, Christensen, EI. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest 1995, 96:1404–1413.
Laurent, G, Carlier, MB, Rollman, B, Van Hoof, F, Tulkens, P. Mechanism of aminoglycoside‐induced lysosomal phospholipidosis: in vitro and in vivo studies with gentamicin and amikacin. Biochem Pharmacol 1982, 31:3861–3870.
Guthrie, OW. Aminoglycoside induced ototoxicity. Toxicology 2008, 249:91–96.
Hobbie, SN, Akshay, S, Kalapala, SK, Bruell, CM, Shcherbakov, D, Bottger, EC. Genetic analysis of interactions with eukaryotic rRNA identify the mitoribosome as target in aminoglycoside ototoxicity. Proc Natl Acad Sci USA 2008, 105:20888–20893.
Kawamoto, K, Sha, SH, Minoda, R, Izumikawa, M, Kuriyama, H, Schacht, J, Raphael, Y. Antioxidant gene therapy can protect hearing and hair cells from ototoxicity. Mol Ther 2004, 9:173–181.
Gilbert, DN, Wood, CA, Kohlhepp, SJ, Kohnen, PW, Houghton, DC, Finkbeiner, HC, Lindsley, J, Bennett, WM. Polyaspartic acid prevents experimental aminoglycoside nephrotoxicity. J Infect Dis 1989, 159:945–953.
Thibault, N, Grenier, L, Simard, M, Bergeron, MG, Beauchamp, D. Attenuation by daptomycin of gentamicin‐induced experimental nephrotoxicity. Antimicrob Agents Chemother 1994, 38:1027–1035.
Du, M, Keeling, KM, Fan, L, Liu, X, Bedwell, DM. Poly‐L‐aspartic acid enhances and prolongs gentamicin‐mediated suppression of the CFTR‐G542X mutation in a cystic fibrosis mouse model. J Biol Chem 2009, 284:6885–6892.
Fielding, RM, Lewis, RO, Moon‐McDermott, L. Altered tissue distribution and elimination of amikacin encapsulated in unilamellar, low‐clearance liposomes (MiKasome). Pharm Res 1998, 15:1775–1781.
Schiffelers, R, Storm, G, Bakker‐Woudenberg, I. Liposome‐encapsulated aminoglycosides in pre‐clinical and clinical studies. J Antimicrob Chemother 2001, 48:333–344.
Sandoval, RM, Reilly, JP, Running, W, Campos, SB, Santos, JR, Phillips, CL, Molitoris, BA. A non‐nephrotoxic gentamicin congener that retains antimicrobial efficacy. J Am Soc Nephrol 2006, 17:2697–2705.
Ben‐Shem, A, Jenner, L, Yusupova, G, Yusupov, M. Crystal structure of the eukaryotic ribosome. Science 2010, 330:1203–1209.
Nudelman, I, Rebibo‐Sabbah, A, Shallom‐Shezifi, D, Hainrichson, M, Stahl, I, Ben‐Yosef, T, Baasov, T. Redesign of aminoglycosides for treatment of human genetic diseases caused by premature stop mutations. Bioorg Med Chem Lett 2006, 16:6310–6315.
Nudelman, I, Rebibo‐Sabbah, A, Cherniavsky, M, Belakhov, V, Hainrichson, M, Chen, F, Schacht, J, Pilch, DS, Ben‐Yosef, T, Baasov, T. Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease‐causing premature stop mutations. J Med Chem 2009, 52:2836–2845.
Nudelman, I, Glikin, D, Smolkin, B, Hainrichson, M, Belakhov, V, Baasov, T. Repairing faulty genes by aminoglycosides: development of new derivatives of geneticin (G418) with enhanced suppression of diseases‐causing nonsense mutations. Bioorg Med Chem 2010, 18:3735–3746.
Rebibo‐Sabbah, A, Nudelman, I, Ahmed, ZM, Baasov, T, Ben‐Yosef, T. In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome. Hum Genet 2007, 122:373–381.
Brendel, C, Belakhov, V, Werner, H, Wegener, E, Gartner, J, Nudelman, I, Baasov, T, Huppke, P. Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model. J Mol Med 2011, 89:389–398.
Arakawa, M, Shiozuka, M, Nakayama, Y, Hara, T, Hamada, M, Kondo, S, Ikeda, D, Takahashi, Y, Sawa, R, Nonomura, Y, et al. Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice (Tokyo). J Biochem 2003, 134:751–758.
Schroeder, SJ, Blaha, G, Moore, PB. Negamycin binds to the wall of the nascent chain exit tunnel of the 50S ribosomal subunit. Antimicrob Agents Chemother 2007, 51:4462–4465.
Uehara, Y, Hori, M, Umezawa, H. Specific inhibition of the termination process of protein synthesis by negamycin. Biochim Biophys Acta 1976, 442:251–262.
Du, L, Damoiseaux, R, Nahas, S, Gao, K, Hu, H, Pollard, JM, Goldstine, J, Jung, ME, Henning, SM, Bertoni, C, et al. Nonaminoglycoside compounds induce readthrough of nonsense mutations. J Exp Med 2009, 206:2285–2297.
Lai, CH, Chun, HH, Nahas, SA, Mitui, M, Gamo, KM, Du, L, Gatti, RA. Correction of ATM gene function by aminoglycoside‐induced read‐through of premature termination codons. Proc Natl Acad Sci USA 2004, 101:15676–15681.
Welch, EM, Barton, ER, Zhuo, J, Tomizawa, Y, Friesen, WJ, Trifillis, P, Paushkin, S, Patel, M, Trotta, CR, Hwang, S, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007, 447:87–91.
Du, M, Liu, X, Welch, EM, Hirawat, S, Peltz, SW, Bedwell, DM. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR‐G542X nonsense allele in a CF mouse model. Proc Natl Acad Sci USA 2008, 105:2064–2069.
Hirawat, S, Welch, EM, Elfring, GL, Northcutt, VJ, Paushkin, S, Hwang, S, Leonard, EM, Almstead, NG, Ju, W, Peltz, SW, et al. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single‐ and multiple‐dose administration to healthy male and female adult volunteers. J Clin Pharmacol 2007, 47:430–444.
Kerem, E, Hirawat, S, Armoni, S, Yaakov, Y, Shoseyov, D, Cohen, M, Nissim‐Rafinia, M, Blau, H, Rivlin, J, Aviram, M, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008, 372:719–727.
Sermet‐Gaudelus, I, Leal, T, DeBoeck, K. PTC124 induces CFTR full‐length production and activity in children with nonsense‐mutation‐mediated CF. J Cyst Fibros 2008, 7:S22.
Wilschanski, M, Miller, LL, Shoseyov, D, Blau, H, Rivlin, J, Aviram, M, Cohen, M, Armoni, S, Yaakov, Y, Pugatch, T, et al. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J 2011.
Clancy, JP, Konstan, MW, Rowe, SM. A phase II study of PTC124 in CF patients harboring premature stop mutations. Ped Pulmonol Suppl 2006, 41:A269.
Finkel, RS. Read‐through strategies for suppression of nonsense mutations in Duchenne/Becker muscular dystrophy: aminoglycosides and ataluren (PTC124). J Child Neurol 2010, 25:1158–1164.
Tan, L, Narayan, SB, Chen, J, Meyers, GD, Bennett, MJ. PTC124 improves readthrough and increases enzymatic activity of the CPT1A R160X nonsense mutation. J Inherit Metab Dis 2011, 34:443–447.
Dranchak, PK, Di Pietro, E, Snowden, A, Oesch, N, Braverman, NE, Steinberg, SJ, Hacia, JG. Nonsense suppressor therapies rescue peroxisome lipid metabolism and assembly in cells from patients with specific PEX gene mutations. J Cell Biochem 2011, 112:1250–1258.
Wang, B, Yang, Z, Brisson, BK, Feng, H, Zhang, Z, Welch, EM, Peltz, SW, Barton, ER, Brown, RH Jr, Sweeney, HL. Membrane blebbing as an assessment of functional rescue of dysferlin‐deficient human myotubes via nonsense suppression. J Appl Physiol 2010, 109:901–905.
Goldmann, T, Overlack, N, Wolfrum, U, Nagel‐Wolfrum, K. PTC124 mediated translational read‐through of a nonsense mutation causing usher type 1C. Hum Gene Ther 2011, 22:537–547.
Auld, DS, Thorne, N, Maguire, WF, Inglese, J. Mechanism of PTC124 activity in cell‐based luciferase assays of nonsense codon suppression. Proc Natl Acad Sci USA 2009, 106:3585–3590.
Auld, DS, Lovell, S, Thorne, N, Lea, WA, Maloney, DJ, Shen, M, Rai, G, Battaile, KP, Thomas, CJ, Simeonov, A, et al. Molecular basis for the high‐affinity binding and stabilization of firefly luciferase by PTC124. Proc Natl Acad Sci USA 2010, 107:4878–4883.
Peltz, SW, Welch, EM, Jacobson, A, Trotta, CR, Naryshkin, N, Sweeney, HL, Bedwell, DM. Nonsense suppression activity of PTC124 (ataluren). Proc Natl Acad Sci USA 2009, 106:E64.
Nicholson, P, Yepiskoposyan, H, Metze, S, Zamudio Orozco, R, Kleinschmidt, N, Muhlemann, O. Nonsense‐mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double‐life of NMD factors. Cell Mol Life Sci 2010, 67:677–700.
Linde, L, Boelz, S, Nissim‐Rafinia, M, Oren, YS, Wilschanski, M, Yaacov, Y, Virgilis, D, Neu‐Yilik, G, Kulozik, AE, Kerem, E, et al. Nonsense‐mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J Clin Invest 2007, 117:683–692.
Maquat, LE, Tarn, WY, Isken, O. The pioneer round of translation: features and functions. Cell 2010, 142:368–374.
Bhuvanagiri, M, Schlitter, AM, Hentze, MW, Kulozik, AE. NMD: RNA biology meets human genetic medicine. Biochem J 2010, 430:365–377.
Lovejoy, CA, Cortez, D. Common mechanisms of PIKK regulation. DNA Repair (Amst) 2009, 8:1004–1008.
Ward, S, Sotsios, Y, Dowden, J, Bruce, I, Finan, P. Therapeutic potential of phosphoinositide 3‐kinase inhibitors. Chem Biol 2003, 10:207–213.
Usuki, F, Yamashita, A, Higuchi, I, Ohnishi, T, Shiraishi, T, Osame, M, Ohno, S. Inhibition of nonsense‐mediated mRNA decay rescues the phenotype in Ullrich`s disease. Ann Neurol 2004, 55:740–744.
Usuki, F, Yamashita, A, Kashima, I, Higuchi, I, Osame, M, Ohno, S. Specific inhibition of nonsense‐mediated mRNA decay components, SMG‐1 or Upf1, rescues the phenotype of ullrich disease fibroblasts. Mol Ther 2006, 14:351–360.
Abraham, RT. The ATM‐related kinase, hSMG‐1, bridges genome and RNA surveillance pathways. DNA Repair (Amst) 2004, 3:919–925.
Durand, S, Cougot, N, Mahuteau‐Betzer, F, Nguyen, CH, Grierson, DS, Bertrand, E, Tazi, J, Lejeune, F. Inhibition of nonsense‐mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P‐bodies. J Cell Biol 2007, 178:1145–1160.
Gong, Q, Stump, MR, Zhou, Z. Inhibition of nonsense‐mediated mRNA decay by antisense morpholino oligonucleotides restores functional expression of hERG nonsense and frameshift mutations in long‐QT syndrome. J Mol Cell Cardiol 2011, 50:223–229.
McIlwain, DR, Pan, Q, Reilly, PT, Elia, AJ, McCracken, S, Wakeham, AC, Itie‐Youten, A, Blencowe, BJ, Mak, TW. Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense‐mediated mRNA decay. Proc Natl Acad Sci USA 2010, 107:12186–12191.
Medghalchi, SM, Frischmeyer, PA, Mendell, JT, Kelly, AG, Lawler, AM, Dietz, HC. Rent1, a trans‐effector of nonsense‐mediated mRNA decay, is essential for mammalian embryonic viability. Hum Mol Genet 2001, 10:99–105.
Weischenfeldt, J, Damgaard, I, Bryder, D, Theilgaard‐Monch, K, Thoren, LA, Nielsen, FC, Jacobsen, SE, Nerlov, C, Porse, BT. NMD is essential for hematopoietic stem and progenitor cells and for eliminating by‐products of programmed DNA rearrangements. Genes Dev 2008, 22:1381–1396.
Sharifi, NA, Dietz, HC. Physiologic substrates and functions for mammalian NMD. In: Maquat, LE, ed. Nonsense‐mediated mRNA Decay. Georgetown, Texas: Landes Bioscience; 2006, 97–109.
Seoighe, C, Gehring, C. Heritability in the efficiency of nonsense‐mediated mRNA decay in humans. PLoS One 2010, 5:e11657.
Ashton, LJ, Brooks, DA, McCourt, PA, Muller, VJ, Clements, PR, Hopwood, JJ. Immunoquantification and enzyme kinetics of α‐L‐iduronidase in cultured fibroblasts from normal controls and mucopolysaccharidosis type I patients. Am J Hum Genet 1992, 50:787–794.
Wraith, JE. The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I. Expert Opin Pharmacother 2005, 6:489–506.
Van Goor, F, Hadida, S, Grootenhuis, PD, Burton, B, Cao, D, Neuberger, T, Turnbull, A, Singh, A, Joubran, J, Hazlewood, A, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX‐770. Proc Natl Acad Sci USA 2009, 106:18825–18830.
Rowe, SM, Varga, K, Rab, A, Bebok, Z, Byram, K, Li, Y, Sorscher, EJ, Clancy, JP. Restoration of W1282X CFTR activity by enhanced expression. Am J Respir Cell Mol Biol 2007, 37:347–356.
Mort, M, Ivanov, D, Cooper, DN, Chuzhanova, NA. A meta‐analysis of nonsense mutations causing human genetic disease. Hum Mutat 2008, 29:1037–1047.

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